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  SHORT TALK I: BrightFocus Foundation Early Career Investigator Session October 10, 2022, 15:50 - 16:50
Glial and vascular contributions to neurodegenerative diseases
Hyperactive somatostatin interneurons near amyloid plaque and cell-type-specific firing deficits in a mouse model of Alzheimer’s disease
Moustafa Moustafa Algamal1,2, Alyssa Russ1,2, Morgan Miller1,2, Steven Hou1,2, Megi Maci1,2, Leon Munting1,2, Qiuchen Zhao1,2, Dmitry Gerashchenko2,3, Brian Bacskai1,2, Ksenia Kastanenka1,2
1Massachusetts General Hospital, Charlestown, USA 2Harvard Medical School, Cambridge, USA
3VA Boston Healthcare System, West Roxbury, USA
TREM2-independent microgliosis promotes tau-mediated neurodegeneration in the presence of ApoE4
Maud Gratuze1, Johannes Schlachetzki2, Nimansha Jain1, Lea Rodriguez1, Clayton Mansel1, Michal Kipnis1, Sydney O'Brien2, Martina P. Pasillas2, Choonghee Lee1, Patrick M. Sullivan4, Marco Colonna3, Christopher K. Glass2, Jason Ulrich1, David M. Holtzman1
1Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St Louis, USA, 2Department of Cellular and Molecular Medicine, University of California, San Diego, USA, 3Department of Pathology and Immunology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St Louis, USA 4Department of Medicine, Duke University Medical Center, Durham Veterans Health Administration Medical Center’s Geriatric Research, Education and Clinical Center, Durham, USA
 Background: In addition to tau and Aβ pathologies, neuroinflammation plays an important role in Alzheimer’s disease (AD). Variants in APOE (E4 isoform) and TREM2 increase AD risk. ApoE4 exacerbates tau- linked neurodegeneration and inflammation in P301S mice and removal of microglia with a CSF1R antagonist blocked tau-dependent neurodegeneration. Microglia adopt a heterogenous population of transcriptomic states (i.e. DAM, IRM, LRM, etc.) in response to pathology, at least some of which (i.e. DAM) are dependent on TREM2. Previously we reported that knockout of TREM2 attenuated neurodegeneration in P301S mice that express mouse Apoe. We initially hypothesized that the ability of TREM2 deletion to dampen tau-mediated microgliosis would result in a decreased microglial inflammatory response and would counteract the detrimental effect of ApoE4 on tau-dependent neurodegeneration. Methods: We generated P301S tau mice expressing ApoE4 (TE4) expressing or not TREM2. Using immunohistochemistry, biochemistry, snRNAseq and ATACseq, we tested in ApoE4 TE4 the consequences of TREM2 deletion on neurodegeneration, tau pathology, and microglia profile. Results: Surprisingly, we report that there is more severe neurodegeneration and tau pathology in TREM2-deficient TE4 mice despite decreased detection of DAM-like TREM2-dependent microglial transcriptomic states. In contrast, we observed elevated expression by microglia of genes reflecting increased lysosomal burden in TE4 mice, independent of TREM2. Discussion: Our data demonstrate that, in the presence of ApoE4, TREM2-independent microglial reactivity is sufficient to drive brain atrophy and synaptic loss in the setting of tauopathy. While TREM2 deletion clearly lowered the expression of a subset of DAM-like genes, a sustained lysosomal expansion remained in microglia and subsequent high synaptic phagocytosis, which can explain, at least partially the absence of neuroprotection. This study raises new important questions about targeting TREM2 and microglia, as a therapeutic approach to treat AD. Conclusions: Our results suggest that TREM2-independent microgliosis facilitates tau-mediated neurodegeneration in the presence of ApoE4.
Alzheimer’s disease (AD) is characterized by progressive memory loss and cognitive decline. These impairments correlate with early alterations in neuronal network activity in AD patients. Disruptions in the activity of individual neurons have been reported in mouse models of amyloidosis. However, the impact of amyloid pathology on distinct neuronal types remains unexplored within intact neuronal circuits. Here we use in vivo calcium imaging with multiphoton microscopy to monitor and compare the spontaneous activity of excitatory and two types of inhibitory interneurons in the cortices of APP/PS1 and control mice. We also determine the relationship between amyloid accumulation and the deficits in spontaneous activity in APP/PS1 mice. We show that somatostatin-expressing (SOM) interneurons are hyperactive, while parvalbumin-expressing interneurons are hypoactive in APP/PS1 mice. Only SOM interneuron hyperactivity correlated with proximity to amyloid plaque. These inhibitory deficits were accompanied by decreased excitatory neuron activity and decreased pairwise activity correlations in APP/PS1 mice. Our study identifies cell-specific neuronal firing deficits in APP/PS1 mice driven by amyloid pathology. These findings highlight the importance of addressing the complexity of neuron-specific deficits to ameliorate circuit dysfunction in Alzheimer’s disease.
Background: Alzheimer’s disease (AD) is the primary cause of dementia, disproportionally affecting women for reasons that are not well understood. Robust neuroinflammation in the brain is a hallmark of the disease and exhibits sex differences that may contribute to sex differences in disease onset and progression. Whether these neuroinflammatory sex differences are due to the complement of sex chromosomes or the circulating gonadally-derived sex hormones is unclear.
Materials and Methods: To dissociate the sex chromosome and gonadal effects on AD-related neuroinflammation, we used the Four-Core Genotype (FCG) mouse model that produces testes- or ovary-bearing mice with either XX or XY sex chromosomes. Female transgenic 5xFAD mice were mated to XY-Sry male FCG mice, and the progeny were aged to 4 or 8 months. The brain parenchyma and the peripheral interfacing regions were assessed by immunohistochemistry, quantitative PCR, and flow cytometry. Splenocytes were isolated and stimulated with a Brefeldin A/ionomycin/PMA cocktail followed by flow cytometry. Results: The contribution of sex chromosomes and circulating gonadal sex hormones varied by age, disease-state, brain region, cell type, and gene. Sex chromosomes accounted for most of the differences in microglia-related measures in aged 5xFAD; FCG mice, while gonads contributed to T cell polarization in aged FCG mice. The differences in
Sex chromosomes and gonads exert differential effects on neuroinflammation in an Alzheimer’s disease mouse model
Erin Reed-Geaghan1, Brad Casali1, Li Lin1, Emily Marsico1,
Lydia Chlpka1, Heleina Dopazo1
1Northeast Ohio Medical University, Rootstown, USA
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